Glutamine and cancer: cell biology, physiology, and clinical opportunities - PubMed (original) (raw)

Review

. 2013 Sep;123(9):3678-84.

doi: 10.1172/JCI69600. Epub 2013 Sep 3.

Affiliations

Review

Glutamine and cancer: cell biology, physiology, and clinical opportunities

Christopher T Hensley et al. J Clin Invest. 2013 Sep.

Abstract

Glutamine is an abundant and versatile nutrient that participates in energy formation, redox homeostasis, macromolecular synthesis, and signaling in cancer cells. These characteristics make glutamine metabolism an appealing target for new clinical strategies to detect, monitor, and treat cancer. Here we review the metabolic functions of glutamine as a super nutrient and the surprising roles of glutamine in supporting the biological hallmarks of malignancy. We also review recent efforts in imaging and therapeutics to exploit tumor cell glutamine dependence, discuss some of the challenges in this arena, and suggest a disease-focused paradigm to deploy these emerging approaches.

PubMed Disclaimer

Figures

Figure 1

Figure 1. Glutamine metabolism as a target for diagnostic imaging and therapy in cancer.

Glutamine is imported via SLC1A5 and other transporters, then enters a complex metabolic network by which its carbon and nitrogen are supplied to pathways that promote cell survival and growth. Enzymes discussed in the text are shown in green, and inhibitors that target various aspects of glutamine metabolism are shown in red. Green arrows denote reductive carboxylation. 18F-labeled analogs of glutamine are also under development as PET probes for localization of tumor tissue. AcCoA, acetyl-CoA; DON, 6-diazo-5-oxo-L-norleucine; GSH, glutathione; NEAA, nonessential amino acids; ME, malic enzyme; OAA, oxaloacetate; TA, transaminase; 968, compound 968; α-KG, α-ketoglutarate.

Figure 2

Figure 2. Model for inter-organ glutamine metabolism in health and cancer.

Organs that release glutamine into the bloodstream are shown in green, and those that consume glutamine are in red; the shade denotes magnitude of consumption/release. For some organs (liver, kidneys), evidence from model systems and/or human studies suggests that there is a change in net glutamine flux during tumorigenesis.

Figure 3

Figure 3. A strategy to integrate glutamine metabolism into the diagnosis, classification, treatment, and monitoring of neuroblastoma.

Neuroblastoma commonly presents in children as an abdominal mass. A standard evaluation of a child with suspected neuroblastoma includes measurement of urine catecholamines, a bone scan, and full-body imaging with meta-iodobenzylguanidine (MIBG), all of which contribute to diagnosis and disease staging. In animal models, a subset of these tumors requires glutamine metabolism. This finding implies that approaches to image, quantify, or block glutamine metabolism (highlighted in red) in human neuroblastoma could be incorporated into the diagnosis and management of this disease. In particular, glutamine metabolic studies may help predict which tumors would respond to therapies targeting glutamine metabolism. HVA, homovanillic acid; VMA, vanillylmandelic acid.

References

    1. Schulze A, Harris AL. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature. 2012;491(7424):364–373. doi: 10.1038/nature11706. - DOI - PubMed
    1. Dang CV. Links between metabolism and cancer. Genes Dev. 2012;26(9):877–890. doi: 10.1101/gad.189365.112. - DOI - PMC - PubMed
    1. Mullen AR, DeBerardinis RJ. Genetically-defined metabolic reprogramming in cancer. Trends Endocrinol Metab. 2012;23(11):552–559. - PMC - PubMed
    1. DeBerardinis RJ, Cheng T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene. 2009;29(3):313–324. doi: 10.1038/onc.2009.358. - DOI - PMC - PubMed
    1. Medina MA, Sanchez-Jimenez F, Marquez J, Rodriguez Quesada A, Nunez de Castro I. Relevance of glutamine metabolism to tumor cell growth. Mol Cell Biochem. 1992;113(1):1–15. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources